CCL21/CCR7 up-regulate vascular endothelial growth factor-D expression via ERK pathway in human non-small cell lung cancer cells

Int J Clin Exp Pathol. 2015 Dec 1;8(12):15729-38. eCollection 2015.

Abstract

Lymphangiogenesis has received considerable attention and become a new research hotspot of tumor metastasis. Recently, C-C chemokine receptor 7 (CCR7) is known to promote metastasis of non-small cell lung cancer (NSCLC) cells into lymph nodes. In this study, we investigated the relationship between CCL21/CCR7 and the lymphangiogenic factor vascular endothelial growth factor (VEGF)-D in human lung cancer cells and its impact on patients' prognosis. We found that CCL21/CCR7 increase the expression of VEGF-D in NSCLC Cell Lines through induced ERK1/2 and Akt phosphorylation. In addition, our study found that the expression levels of CCR7 and CCL21 were correlated with VEGF-D, lymphatic vessels density (LVD), clinical stages, lymph node metastasis, and patient Survival in 90 human non-small cell lung cancer (NSCLC) specimens. Taken together, our results provide evidence that CCL21/CCR7 induce VEGF-D up-regulation and promote lymphangiogenesis via ERK/Akt pathway in lung cancer.

Keywords: CCR7; NSCLC; VEGF-D; lymphangiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / enzymology*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Non-Small-Cell Lung / secondary
  • Carcinoma, Non-Small-Cell Lung / therapy
  • Cell Line, Tumor
  • Chemokine CCL21 / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kaplan-Meier Estimate
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy
  • Lymphangiogenesis
  • Lymphatic Metastasis
  • Lymphatic Vessels / pathology
  • Male
  • Middle Aged
  • Neoplasm Staging
  • RNA Interference
  • Receptors, CCR7 / genetics
  • Receptors, CCR7 / metabolism*
  • Signal Transduction
  • Time Factors
  • Transfection
  • Up-Regulation
  • Vascular Endothelial Growth Factor D / metabolism*

Substances

  • CCL21 protein, human
  • CCR7 protein, human
  • Chemokine CCL21
  • Receptors, CCR7
  • VEGFD protein, human
  • Vascular Endothelial Growth Factor D
  • Extracellular Signal-Regulated MAP Kinases